The overall goal of this project is to examine whether exposure to environmental pollutants, specifically volatile organic compounds (VOCs), induces/exacerbates cardiometabolic disease (CMD) by causing systemic insulin resistance and low grade inflammation. Insulin is a master regulator of metabolism and energy disposition, and dysregulation of insulin signaling is associated with the development of obesity and Type 2 diabetes (T2D), which are robust contributors to atherogenesis and heart disease. Recent research has identified a pathogenic continuum between the development of insulin resistance, hepatic steatosis, dyslipidemia and cardiovascular disease. We postulate that environmental pollutants/toxins can either directly cause CMD or interact with obesity and poor nutrition to cause/exacerbate CMD. We have published initial experimental human/rodent data to support this concept, and further preliminary animal data are presented in Project #2. Here, we present important human preliminary results from a unique database/specimen bank of plant workers exposed to high levels of certain VOCs, especially vinyl chloride. The Toxicology Specimen and Databank provides the opportunity for a novel cross-sectional study evaluating the effects of vinyl chloride and other VOCs on the development of insulin resistance and fatty liver (Aim 1a). We will examine our death certificate data to evaluate the effects of VOC exposure on all cause and cardiac deaths (Aim 1b). We will also perform a retrospective/prospective study using samples obtained over a ~40-year period of time to correlate the development of insulin resistance with outcome measures of the CMD and predictors of risk (including occupational exposure, personal exposure, and novel markers of metabolic injury that we have developed? Aim 1c). We will also be able to enroll residents from VOC hot spots including the Lees Lane superfund site in a prospective longitudinal evaluation of the impact of lower levels of exposure and the impact of obesity/nutrition on the progression of CMD (Aim 2). We are able to perform these studies because of an established database, continued linkages with industry for nearly 40 years, and ongoing interactions with community leaders and residents which provide a highly-novel opportunity to assess the cardiometabolic effects of VOCs over a range of exposures.